Chapter 150. Urticaria and Angioedema

A 26-year-old man was given trimethoprim-sulfamethoxazole for sinusitis and broke out in hives 1 week later. The hives were all over his trunk and arms (Figures 150-1 and 150-2). He had no airway compromise and had only urticaria without angioedema. His sinus symptoms were mostly resolved, so he was told to stop the antibiotic and take an oral antihistamine. The H1-blocker gave him relief of symptoms and the wheals disappeared over the next 2 days.

Urticaria and angioedema are a heterogeneous group of diseases that cause swelling of the skin and other soft tissues. They both result from a large variety of underlying causes, are elicited by a great diversity of factors, and present clinically in a highly variable way.1 Standard hives with transient wheals is the most common manifestation of urticaria.

Hives.

• It is estimated that 15% to 25% of the population may have urticaria sometime during their lifetime.2
• Urticaria affects 6% to 7% of preschool children and 17% of children with atopic dermatitis.2
• Among all age groups, approximately 50% have both urticaria and angioedema, 40% have isolated urticaria, and 10% have angioedema alone.2
• Acute urticaria is defined as less than 6 weeks' duration. A specific cause is more likely to be identified in acute urticaria.2
• The cause of chronic urticaria (>6 weeks' duration) is determined in less than 20% of cases.2
• Chronic urticaria is twice as common in women as in men.3
• Chronic urticaria predominantly affects adults.3
• Up to 40% of patients with chronic urticaria of more than 6 months' duration still have urticaria 10 years later.3

• The pathophysiology of angioedema and urticaria can be immunoglobulin (Ig) E mediated, complement mediated, related to physical stimuli, autoantibody mediated, or idiopathic.
• These mechanisms lead to mast cell degranulation resulting in the release of histamine. The histamine and other inflammatory mediators produce the wheals, edema, and pruritus.
• Urticaria is a dynamic process in which new wheals evolve as old ones resolve. These wheals result from localized capillary vasodilation, followed by transudation of protein-rich fluid into the surrounding skin. The wheals resolve when the fluid is slowly reabsorbed.
• Angioedema is an edematous area that involves transudation of fluid into the dermis and subcutaneous tissue (Figures 150-3 and 150-4).

The following etiologic types exist:

• Immunologic—IgE mediated, complement mediated. Occurs more often in patients with an atopic background. Antigens are most commonly foods or medications. The most common foods are milk, nuts, wheat, and shellfish.
• Physical urticaria—Dermatographism, cold, cholinergic, solar, pressure, vibratory urticaria (Figures 150-5 and 150-6).
• Urticaria caused by mast cell-releasing agents—Mastocytosis, urticaria pigmentosa (Figures 150-7 and 150-8).
• Urticaria associated with vascular/connective tissue autoimmune disease.
• Hereditary angioedema is a potentially life-threatening disorder that is inherited in an autosomal dominant manner. In this disease, angioedema occurs without urticaria (Figure 150-9).

Clinical Features

• Symptoms include itching, burning, and stinging.
• Wheals vary in size from small, 2-mm papules of cholinergic urticaria (Figure 150-6) to giant hives where a single wheal may cover a large portion of the trunk.
• The wheal may be all red or white, or the border may be red with the remainder of the surface white.
• Wheals may be annular (Figures 150-10 and 150-11).
• If dermatographism is present, one can write on the skin and be able to see the resulting words or shapes (Figure 150-5).
• If you suspect urticaria pigmentosa, stroke a lesion with the wooden end of a cotton-tipped applicator. This induces erythema of the plaque and the wheal is confined to the stroke site. This is called Darier sign (Figure 150-12).

Typical Distribution

• Angioedema is seen more often on the face and is especially found around the mouth and eyes (Figures 150-3 and 150-4). Sometimes angioedema can occur on the genitals or the trunk (Figure 150-13).
• Urticaria can be found anywhere on the body and is often on the trunk and extremities (Figures 150-1 and 150-2).

Laboratory Studies

Consider tests that might help reveal the cause of the urticaria and/or angioedema.

• Order complement studies to investigate for hereditary or acquired C1 esterase inhibitor deficiency when angioedema occurs repeatedly without urticaria (Figure 150-9).
• Consider allergen skin testing and/or in vitro tests for when the history reveals that urticaria/angioedema occurs after direct contact with a suspected allergen.
• Punch biopsy of the involved area may be used to diagnose urticarial vasculitis or mastocytosis.

• Insect bites—A good history and physical examination should help to distinguish between insect bites and urticaria.
• Erythema multiforme like urticaria can occur in response to an allergic/immunologic reaction to medications, infections, and neoplasms. The classic lesion of erythema multiforme is the target lesion in which there is disruption of the epithelium in the center. This disruption may be a vesicle, bulla, or erosion. Do not confuse annular lesions or concentric rings with erythema multiforme if the epidermis is intact (Figure 150-11 is not erythema multiforme) (see Chapter 177, Erythema Multiforme, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis).
• Urticarial vasculitis typically has lesions that last longer than 24 hours. The lesions are found more commonly on the lower extremities, and when they heal, they often leave hyperpigmented areas. Causes range from a hypersensitivity vasculitis, such as Henoch-Schönlein purpura, to underlying connective tissue disease (Figure 150-14).2
• Mast cell releasability syndromes are syndromes in which there are too many mast cells in the skin or other organs of the body. These include cutaneous mastocytosis and urticaria pigmentosa (Figures 150-7, 150-8, and 150-12).
• Pruritic urticarial papules and plaques of pregnancy can be differentiated from urticaria in pregnancy because the eruption remains fixed and increases in intensity until delivery (Figure 150-15) (see Chapter 75, Pruritic Urticarial Papules and Plaques of Pregnancy).
• Pemphigoid gestationis can have lesions that are urticarial. However, it also has bullae that distinguish it from urticaria and of course the patient is pregnant or postpartum (see Chapter 76, Pemphigoid Gestationis).

Nonpharmacologic Therapy

• Avoid any causative agent, medication, stimulus, or antigen if found. SOR B
• Angiotensin-converting enzyme inhibitors (ACEIs) are especially prone to causing angioedema so should be stopped as soon as possible when suspected to be causative of angioedema or urticaria (Figure 150-3).1 SOR A Even an angiotensin receptor blocker (ARB) can cause angioedema and should be suspected in a patient on this class of medication (Figure 150-16).
• In chronic urticaria, patients may benefit from avoidance of potential urticarial precipitants such as aspirin, NSAIDs (Figure 150-17), opiates, and alcohol.1 SOR B
• Infections may be a cause, an aggravating factor, or an unassociated bystander.1 Look for sources of chronic infections such as parasitic infections, dental infections, GI infections, respiratory infections, and tinea pedis. Treat these, as it is possible, but unproven, that they can contribute to the chronic urticaria. SOR C
• Stop all unnecessary nonprescription medications, supplements, and vitamins in chronic urticaria. SOR C
• Avoidance of physical stimuli for the treatment of physical urticaria is desirable, but not always possible (observational studies only).1 SOR B
• Stress reduction techniques may help in chronic urticaria but this is unproven. SOR C

Antihistamines

• Low-sedating, second-generation antihistamines should be prescribed as a first-line treatment for chronic urticaria.4-6 SOR A
• Increasing the dose of cetirizine from 10 mg to 20 mg daily produced a significant improvement in the severity of wheal and itching in urticaria refractory to the standard doses of antihistamines.7 SOR B
• The British guidelines even suggest using antihistamines at up to quadruple the manufacturers' recommended dosages before changing to an alternative therapy. They also recommend waiting up to 4 weeks to allow full effectiveness of the antihistamines before considering referral to a specialist.1 SOR C
• All patients should be offered the choice of at least two low-sedating H1 antagonists because responses and tolerance vary between individuals.8 SOR A
• Addition of a sedating antihistamine at night may help patients sleep better, although they probably add little to existing H1 receptor blockade.8
• The addition of an H2 antagonist may give better control of urticaria than H1 antagonists alone, SOR B although a benefit is not always seen.8 In one study, adding H2 blockers to H1 antagonists resulted in improvement of certain cutaneous outcomes for patients presenting with acute allergic syndromes to an emergency department.9 SOR B
• When initial antihistamines are not working, consider doxepin, an antidepressant and potent H1 antagonist.10 SOR B Its use is limited by the side effects of sedation and dry mouth. Start with 10 mg doxepin in the evening and titrate up as needed and tolerated.
• Low-sedating antihistamines seem to be effective in the treatment of acquired cold urticaria by significantly reducing the presence of wheals and pruritus after cold exposure.11 SOR A

Corticosteroids

• Oral corticosteroids should be restricted to short courses for severe acute urticaria or angioedema affecting the mouth (e.g., prednisone 60 mg/day for 3 to 4 days in adults).8,12 SOR B
• Short tapering courses of oral steroids over 3 to 4 weeks may be necessary for urticarial vasculitis and severe delayed pressure urticaria.
• Long-term oral corticosteroids should not be used in chronic urticaria. It is better to use oral cyclosporine if needed as it has a far better risk-to-benefit ratio compared with steroids.1,8
• A randomized controlled trial showed that clobetasol 0.05% in a foam formulation was safe and effective in the short-term treatment of patients with delayed pressure urticaria.13 SOR B

Immunomodulatory Agents

• Immunosuppressive therapies for autoimmune urticaria should be restricted to patients with disabling disease who have not responded to optimal conventional treatments.6
• A retrospective study of methotrexate in 8 patients with recalcitrant chronic urticaria indicated that methotrexate was both safe and effective, with a mean dose of 15 mg methotrexate/week. Seven of 8 patients achieved a complete response and 5 of 8 remained disease-free after methotrexate was stopped.14 SOR B
• Cyclosporine, plasmapheresis, anti-IgE (Omalizumab), and intravenous immunoglobulin have been used in severe recalcitrant cases.1 SOR C
• Plasmapheresis is very costly and should be reserved for autoantibody-positive chronic spontaneous urticaria patients.1

Others

• Epinephrine is valuable in severe acute urticaria or angioedema, especially if there is a suspicion of airway compromise or anaphylaxis.
• The evidence for leukotriene modifiers in the treatment of urticaria is poor. SOR C
• Ecallantide is a new plasma kallikrein inhibitor for the subcutaneous treatment of acute attacks of hereditary angioedema.15 SOR B
• Antiinflammatory drugs, such as colchicine, dapsone and sulfasalazine, have been reported as helpful in uncontrolled trials or case series.1

In most cases, we are not able to find the cause of urticaria. This is especially true for chronic urticaria. Fortunately, most chronic urticaria will subside over time and there are medicines to treat the condition until it runs its course. If one medication doesn't work keep your follow-up visits to try other medications. Carefully observe for causative agents.

Follow-up is especially needed when the urticaria/angioedema persist or recur.

Patient Resources

• eMedicineHealth.com is a consumer health site with information and support groups—http://www.emedicinehealth.com/hives_and_angioedema/article_em.htm.

Provider Resources

• Well written guideline based upon a joint initiative of a number of European dermatology, allergy, and immunology organizations—http://onlinelibrary.wiley.com/doi/10.1111/j.1398-9995.2009.02178.x/full.